B lymphocyte development and differentiation are important in establishing and maintaining the immune response in mammalian species. Mature, immunoglobulin-secreting B cells are the end result of a complex process of differentiation from hematopoietic progenitors that originate in the bone marrow.
The differentiation program of B lymphocytes involves a complex set of molecular signals, perhaps the most fundamental of which is productive rearrangement of the immunoglobulin (Ig) variable domain genetic locus. During B cell ontogeny, productive rearrangement of the Ig gene locus appears to be the central event permitting progression of B cell differentiation to the mature stages of the memory B cell and Ig-secreting plasma cell; however, correct joining of the V, D and J regions of the heavy chain variable domain with the C region to form functional heavy chain polypeptides does not occur in every progenitor B cell.
While positive selection is thought to facilitate continued viability and expansion of B cells possessing productive Ig rearrangements, it has been shown that uncharacterized mechanisms of negative selection, other than apoptosis regulated by bcl-2 and fas, are also involved in the elimination of cells containing nonproductive Ig gene rearrangements (Tarlinton, 1994). In fact, a majority of candidate B cells fail in this early differentiative step and are eliminated from the B cell repertoire. In contrast, and possibly as a result of the breakdown of the various forms of elimination, cells in almost any stage of B cell differentiation are known to undergo neoplastic immortalization, resulting in the appearance of various forms of leukemia and lymphoma when the body's ability to identify and destroy such cells breaks down (Lukens, 1993). Thus, means for early detection of malformed cells would be useful in effecting early diagnosis and treatment of leukemia. Forming the basis for the present invention is the identification of a novel gene, termed "B4B." Even though expression of B4B mRNA can be detected in multiple tissues, expression of the protein which is encoded by the B4B gene is tightly restricted to a subset of progenitor/pre-B cells which do not express cytoplasmic .mu.-chains. Such cells may therefore lack productive Ig gene rearrangements, and may be superfluous to the body. According to an important feature of the present invention it is further recognized that expression in cells of B4B induces inhibition of cellular growth. Accordingly, B4B antigen expression serves as a useful cell marker, and induction of such expression may prevent unwanted cellular proliferation. These and other useful features of the invention are described in the sections that follow.